This invention relates to the use of pyrazole derivatives in the manufacture of a reverse transcriptase inhibitor or modulator, to certain novel such pyrazole derivatives and to processes for the preparation of and compositions containing such novel derivatives.
The present pyrazole derivatives bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds which interfere with the function of this enzyme have shown utility in the treatment of conditions including AIDS. There is a constant need to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase since the virus is able to mutate, becoming resistant to their effects.
The present pyrazole derivatives are useful in the treatment of a variety of disorders including those in which reverse transcriptase is implicated. Disorders of interest include those caused by Human Immunodificiency Virus (HIV) and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS).
European Patent Application EP 0 786 455 A1 discloses a class of imidazole compounds which inhibit the growth of HIV. A class of N-phenylpyrazoles which act as reverse transcriptase inhibitors are disclosed in J. Med. Chem., 2000, 43, 1034. Antiviral activity is ascribed to a class of N-(hydroxyethyl)pyrazole derivatives in U.S. Pat. No. 3,303,200.
According to the present invention there is provided the use of a compound of the formula 
or a pharmaceutically acceptable salt or solvate thereof, wherein
either (i) R1 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, halo, xe2x80x94CN, xe2x80x94OR7,
xe2x80x94OR8, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5xe2x80x94NR5, xe2x80x94NR5COR5,
NR5xe2x80x94COxe2x80x94(C1-C6 alkylene)xe2x80x94OR5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R8, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, xe2x80x94CN,
xe2x80x94OR5, xe2x80x94OR8, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR8R9,
xe2x80x94NR5COR5, xe2x80x94NR5COR6, xe2x80x94NR5COR8, xe2x80x94SO2NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R6, and
R2 is H or xe2x80x94Yxe2x80x94Z,
or, (ii) R1 and R2, when taken together, represent unbranched C3-C4 alkylene, optionally wherein one methylene group of said C3-C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R5 or R8;
Y is a direct bond or C1-C3 alkylene;
Z is R10 or, where Y is C1-C3 alkylene, Z is xe2x80x94NR5COR10, xe2x80x94NR5CONR5R10,
xe2x80x94NR5CONR5COR10 or xe2x80x94NR5SO2R10;
R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, xe2x80x94CN, halo, xe2x80x94OR7, xe2x80x94CO2R5,
xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94NR5CONR5R5,
xe2x80x94NR5SO2R7 or R6, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, xe2x80x94CN, xe2x80x94OR5, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5,
xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94SO2NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R6;
R4 is phenyl or pyridyl, each being optionally substituted by R6, halo, xe2x80x94CN, C1-C6 alkyl, fluoro-(C1-C6)-alkyl, C3-C7 cycloalkyl or C1-C6 alkoxy;
each R5 is independently either H, C1-C6 alkyl, C3-C7 cycloalkyl, fluoro-(C1-C6)-alkyl, phenyl or benzyl, or, when two such groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C1-C6 alkyl or C3-C7 cycloalkyl and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen atom not taken together with the two R5 groups to form the ring by xe2x80x94COR7 or xe2x80x94SO2R7;
R6 is a four to six-membered, aromatic, partially unsaturated or saturated heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by xe2x80x94OR5, xe2x80x94NR5R5, xe2x80x94CN, oxo, C1-C6 alkyl, C3-C7 cycloalkyl, xe2x80x94COR7 or halo;
R7 is C1-C6 alkyl, C3-C7 cycloalkyl, fluoro-(C1-C6)-alkyl, phenyl or benzyl;
R8 is C1-C6 alkyl substituted by phenyl, phenoxy, pyridyl or pyrimidinyl, said phenyl, phenoxy, pyridyl and pyrimidinyl being optionally substituted by halo,
xe2x80x94CN, xe2x80x94CONR5R5, xe2x80x94SO2NR5R5, xe2x80x94NR5SO2R7, xe2x80x94NR5R5, xe2x80x94(C1-C6 alkylene)xe2x80x94NR5R5, C1-C6 alkyl, fluoro-(C1-C6)-alkyl, C3-C7 cycloalkyl or C1-C6 alkoxy;
R9 is H, C1-C6 alkyl or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by xe2x80x94OR5, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94CONR5R5 or R6;
R10 is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, phenyl, benzyl or C-linked R6, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, xe2x80x94OR5, xe2x80x94OR12, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5,
xe2x80x94C(xe2x95x90NR5)NR5OR5, xe2x80x94CONR5NR5R5, xe2x80x94OCONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5R12, xe2x80x94NR5COR5,
xe2x80x94NR5CO2R7, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5, xe2x80x94NR5SO2R7, xe2x80x94SO2NR5R5 or R6;
X is xe2x80x94CH2xe2x80x94, xe2x80x94CHR11xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
R11 is C1-C6 alkyl, C3-C7 cycloalkyl, fluoro-(C1-C6)-alkyl or C1-C6 alkoxy; and
R12 is C1-C6 alkyl substituted by R6, xe2x80x94OR5, xe2x80x94CONR5R5, xe2x80x94NR5COR5 or xe2x80x94NR5R5;
in the manufacture of (a) a reverse transcriptase inhibitor or modulator or (b) a medicament for the treatment of a human immunodeficiency viral (HIV), or genetically related retroviral, infection or a resulting acquired immunodeficiency syndrome (AIDS).
The present invention also provides a novel compound of the formula 
or a pharmaceutically acceptable salt or solvate thereof, wherein
either (i) R1 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, halo, xe2x80x94CN, xe2x80x94OR7, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94NR5COxe2x80x94(C1-C6 alkylene)-OR5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R6, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, xe2x80x94CN, xe2x80x94OR5, xe2x80x94OR8, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR8R9, xe2x80x94NR5COR5, xe2x80x94NR5COR6, xe2x80x94NR5COR8, xe2x80x94SO2NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R6 and
R2 is xe2x80x94Yxe2x80x94Z,
or, R1 and R2, when taken together, represent unbranched C3-C4 alkylene, optionally wherein one methylene group of said C3-C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R5 or R8,
and R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, xe2x80x94CN, halo, xe2x80x94OR7, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2NR7 or R6, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, xe2x80x94CN, xe2x80x94OR5, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94SO2NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7or R6,
or (ii) R1 and R3 are each independently C1-C6 alkyl, C3-C7 cycloalkyl or halo-(C1-C6 alkyl), and R2 is H,
provided that
(a) for definition (i), R1 and R3 are not both H,
(b) for definition (i), R1 and R3 are not both optionally substituted phenyl, as defined therein,
(c) for definition (i), when R1 and R3 are both methyl, R2 is not phenyl or methyl, and
(d) for definition (ii), R1 and R3 are not both methyl;
Y is a direct bond or C1-C3 alkylene;
Z is R10 or, where Y is C1-C3 alkylene, Z is xe2x80x94NR5COR10, xe2x80x94NR5CONR5R10,
xe2x80x94NR5CONR5COR10 or xe2x80x94NR5SO2R10;
R4 is phenyl or pyridyl, each substituted by at least one substituent selected from halo, xe2x80x94CN, C1-C6 alkyl, fluoro-(C1-C6)-alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy;
each R5 is independently either H, C1-C6 alkyl, C3-C7 cycloalkyl, fluoro-(C1-C6)-alkyl, phenyl or benzyl, or, when two such groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C1-C6 alkyl or C3-C7 cycloalkyl and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen atom not taken together with the two R5 groups to form the ring by xe2x80x94COR7 or xe2x80x94SO2R7;
R6 is a four to six-membered, aromatic, partially unsaturated or saturated heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by xe2x80x94OR5, xe2x80x94NR5R5, xe2x80x94CN, oxo, C1-C6 alkyl, C3-C7 cycloalkyl, xe2x80x94COR7 or halo;
R7 is C1-C6 alkyl, C3-C7 cycloalkyl, fluoro-(C1-C6)-alkyl, phenyl or benzyl;
R8 is C1-C6 alkyl substituted by phenyl, pyridyl or pyrimidinyl, said phenyl, pyridyl and pyrimidinyl being optionally substituted by halo, xe2x80x94CN, xe2x80x94CONR5R5, xe2x80x94SO2NR5R5,
xe2x80x94NR5SO2R7, xe2x80x94NR5R5, xe2x80x94(C1-C6 alkylene)-NR5R5, C1-C6 alkyl, flouro-(C1-C6)-alkyl, C3-C7 cycloalkyl or C1-C6 alkoxy;
R9 is H, C1-C6 alkyl or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by xe2x80x94OR5, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94CONR5R5 or R6;
R10 is (a) benzyl or C-linked R6, said benzyl being optionally substituted by halo, xe2x80x94OR5, xe2x80x94OR12, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94C(xe2x95x90NR5)NR5OR5, xe2x80x94CONR5NR5R5, xe2x80x94CONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5R12, xe2x80x94NR5COR5, xe2x80x94NR5CO2R7, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5, xe2x80x94NR5SO2R7, xe2x80x94SO2NR5R5 or R6, or (b) when R1 and R3 are each independently C1-C6 alkyl, C3-C7 cycloalkyl or halo-(C1-C6 alkyl), R10 is phenyl, C1-C6 alkyl or C3-C7 cycloalkyl each being optionally substituted by halo, xe2x80x94OR5, xe2x80x94OR12, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94C(xe2x95x90NR5)NR5OR5, xe2x80x94CONR5NR5R5, xe2x80x94OCONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5R12, xe2x80x94NR5COR5, xe2x80x94NR5CO2R7, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5, xe2x80x94NR5SO2R7, xe2x80x94SO2NR5R5 or R6;
X is xe2x80x94CH2xe2x80x94, xe2x80x94CHR11xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
R11 is C1-C6 alkyl, C3-C7 cycloalkyl, fluoro-(C1-C6)-alkyl or C1-C6 alkoxy; and
R12 is C1-C6 alkyl substituted by R6, xe2x80x94OR5, xe2x80x94CONR5R5, xe2x80x94NR5COR5 or xe2x80x94NR5R5.
In the above definitions, halo means fluoro, chloro, bromo or iodo. Unless otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-buten-1-yl. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene and 1,3-propylene. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. xe2x80x98C-linkedxe2x80x99 used in the definition of R10 means that the R10 substituent is attached through a ring carbon atom. Where R1 and R2 are taken together, they form, along with the nitrogen atom and the carbon atom of the pyrazole ring to which they are attached, a 5- or 6-membered ring.
The pharmaceutically acceptable salts of the compounds of the formula (I) and the compounds of the formula (Ib) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, para-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.
The pharmaceutically acceptable solvates of the compounds of the formula (I) and the compounds of the formula (Ib), and the salts thereof, include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) and the compounds of the formula (Ib) are polymorphs thereof.
A compound of the formula (I) or a compound of the formula (Ib) may contain one or more asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and the compounds of the formula (Ib) together with, where appropriate, the individual tautomers thereof, and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or high performance liquid chromatography (HPLC) of a stereoisomeric mixture of a compound of the formula (I) or a compound of the formula (Ib) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) or a compound of the formula (Ib) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
Preferred individual compounds according to the invention include the Examples below.
Particularly preferred individual compounds according to the invention include
2-{4-[(3,5-dichlorophenyl)sulfanyl]-3,5-dimethyl-1H-pyrazol-1-yl}ethanol;
2-[4-[(3,5-dichlorophenyl)sulfanyl]-3-ethyl-5-(hydroxymethyl)-1H-pyrazol-1-yl]ethanol; and
2-{4-[(3,5-dichlorophenyl)sulfanyl]-3,5-diethyl-1H-pyrazol-1-yl}ethanol.
The following preferred features of the invention relate both to compounds of the formula (I) and compounds of the formula (Ib).
Preferably, R1 is C1-C6 alkyl, xe2x80x94OR7, xe2x80x94CO2R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COxe2x80x94(C1-C6 alkylene)-OR5 or R6, said C1-C6 alkyl being optionally substituted by halo, xe2x80x94CN, xe2x80x94OR5, xe2x80x94OR8, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR8R9, xe2x80x94NR5COR5, xe2x80x94NR5COR6, xe2x80x94NR5COR8, xe2x80x94SO2NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R6.
Preferably, R1 is C1-C6 alkyl, xe2x80x94OR7, xe2x80x94CO2R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COxe2x80x94(C1-C6 alkylene)-OR5 or R6, said C1-C6 alkyl being optionally substituted by halo or xe2x80x94OR5.
Preferably, R1 is C1-C3 alkyl, xe2x80x94OCH3, xe2x80x94CO2(C1-C2 alkyl), xe2x80x94NHCO2(C1-C2 alkyl), xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHCOCH2OCH3 or furanyl, said C1-C3 alkyl being optionally substituted by fluoro or xe2x80x94OH.
Preferably, R1 is methyl, ethyl, prop-2-yl, hydroxymethyl, trifluoromethyl, xe2x80x94OCH3, xe2x80x94CO2CH2CH3, xe2x80x94NHCO2CH2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, xe2x80x94NHCOCH2OCH3 or furan-2-yl.
Preferably, R1 is ethyl.
Preferably, R1 is methyl, ethyl, trifluoromethyl or xe2x80x94CH2NHCH2(4-cyanophenyl).
Preferably, R2 is H, C1-C6 alkyl, xe2x80x94(C1-C3 alkylene)-NR5COxe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C3 alkylene)-NR5CONR5xe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C3 alkylene)-NR5CONR5CO-(phenyl), xe2x80x94(C1-C3 alkylene)-NR5SO2(C-linked R6), xe2x80x94(C1-C3 alkylene)-NR5CO(C-linked R6), xe2x80x94(C1-C3 alkylene)-NR5CO-(phenyl), each C1-C6 alkyl and phenyl being optionally substituted by halo, xe2x80x94OR5, xe2x80x94OR12, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94C(xe2x95x90NR5)NR5OR5, xe2x80x94CONR5NR5R5, xe2x80x94OCONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5R12, xe2x80x94NR5COR5, xe2x80x94NR5CO2R7, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5, xe2x80x94NR5SO2R7, xe2x80x94SO2NR5R5 or R6.
Preferably, R2 is H, C1-C6 alkyl, xe2x80x94(C1-C3 alkylene)-NR5COxe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C3 alkylene)-NR5CONR5xe2x80x94(C1-C6 alkyl), xe2x80x94(C1-C3 alkylene)-NR5CONR5CO-(phenyl),
xe2x80x94(C1-C3 alkylene)-NR5SO2R6, xe2x80x94(C1-C3 alkylene)-NR5COR6, xe2x80x94(C1-C3 alkylene)-NR5CO-(phenyl), each C1-C6 alkyl and phenyl being optionally substituted by halo, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94OCONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5 or R6.
Preferably, R2 is H, C1-C3 alkyl, xe2x80x94(C1-C2 alkylene)-NHCOxe2x80x94(C1-C3 alkyl), xe2x80x94(C1-C2 alkylene)-NHCONHxe2x80x94(C1-C3 alkyl), xe2x80x94(C1-C2 alkylene)-NHCONHCO-(phenyl), xe2x80x94(C1-C2 alkylene)-NHSO2R6, xe2x80x94(C1-C2 alkylene)-NHCOR6, xe2x80x94(C1-C2 alkylene)-NHCO-(phenyl), each C1-C3 alkyl and phenyl being optionally substituted by fluoro, xe2x80x94OH, xe2x80x94O(C1-C6 alkyl), xe2x80x94CN, xe2x80x94CO2(C1-C6 alkyl), xe2x80x94CONH2, xe2x80x94OCONH2, xe2x80x94OCONHCO2Ph, xe2x80x94NH2, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94NHCONH2, xe2x80x94NHCOCONH2 or R6.
Preferably, R2 is H, xe2x80x94CH2OH, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2CH2OH, xe2x80x94CH2OCONH2, xe2x80x94CH2CH2OCONH2, xe2x80x94CH2OCONHCO2Ph, xe2x80x94CH2CO2CH2CH3, xe2x80x94CH2CH2CO2CH3, xe2x80x94CH2CH2CO2CH2CH3, xe2x80x94CH2CH2CONH2, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2CH2NH2, xe2x80x94CH2CH2NHCOCHF2, xe2x80x94CH2CH2NHCOCH2CN, xe2x80x94CH2CH2NHCOCH2N(CH3)2, xe2x80x94CH2CH2NHCOCH2OCH3, xe2x80x94CH2CH2NHCOCH2OH, xe2x80x94CH2CH2NHCOCH2OCH2CH3, xe2x80x94CH2CH2NHCOCH2NHCONH2, xe2x80x94CH2CH2NHCOCONH2, xe2x80x94CH2CH2NHCONHCH2CH2CH3, xe2x80x94CH2CH2NHCONHCOPh, xe2x80x94CH2CH2NHCONHCO(2,6-difluorophenyl), xe2x80x94CH2CH2NHSO2(2,4-dihydroxypyrimidin-5-yl), xe2x80x94CH2CH2NHSO2(1-methylimidazol4-yl), xe2x80x94CH2CH2NHCO(tetrahydrofuran-2-yl), xe2x80x94CH2CH2NHCO(1,5-dimethylpyrazol-3-yl), xe2x80x94CH2CH2NHCOCH2(tetrazol-1-yl), xe2x80x94CH2CH2NHCOPh, xe2x80x94CH2CH2NHCO(pyridin-2-yl), xe2x80x94CH2CH2NHCO(pyrimidin-2-yl), xe2x80x94CH2CH2NHCO(2-fluorophenyl), xe2x80x94CH2CH2NHCO(3-hydroxyphenyl), xe2x80x94CH2CH2NHCO(3-hydroxypyridazin-6-yl), xe2x80x94CH2CH2NHCO(2-hydroxypyridin-6-yl), xe2x80x94CH2CH2NHCO(2-oxo-2H-pyran-5-yl) or xe2x80x94CH2CH2NHCO(1,2,3-thiadiazol-4-yl).
Preferably, R2 is H, methyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2CH2OH, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2CH2NH2, xe2x80x94CH2CN, xe2x80x94CH2CH2OCH3, xe2x80x94CH2CONH2, xe2x80x94CH2CH2NHCOCH2OCH3 or azetidin-3-yl.
Preferably, R2 is xe2x80x94CH2CH2OH, xe2x80x94CH2CH2NH2, xe2x80x94CH2CN or azetidin-3-yl.
Preferably, R3 is C1-C6 alkyl, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94NR5CO2R7 or xe2x80x94NR5R5, said C1-C6 alkyl being optionally substituted by halo, xe2x80x94CN, xe2x80x94OR5, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94NR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5COR5, xe2x80x94SO2NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5SO2R7 or R6.
Preferably, R3 is C1-C6 alkyl, xe2x80x94CO2R5, xe2x80x94CONR5R5, xe2x80x94NR5CO2R5 or xe2x80x94NR5R5, said C1-C6 alkyl being optionally substituted by halo, xe2x80x94CN or xe2x80x94OR5.
Preferably, R3 is C1-C3 alkyl, xe2x80x94CO2(C1-C2 alkyl), xe2x80x94CONH2, xe2x80x94NHCO2(C1-C4 alkyl), xe2x80x94N(CH3)2 or xe2x80x94NH2, said C1-C3 alkyl being optionally substituted by halo, xe2x80x94CN or xe2x80x94OH.
Preferably, R3 is methyl, ethyl, prop-2-yl, hydroxymethyl, cyanomethyl, trifluoromethyl, xe2x80x94CO2CH2CH3, xe2x80x94CONH2, xe2x80x94NHCO2C(CH3)3, xe2x80x94N(CH3)2 or xe2x80x94NH2.
Preferably, R3 is methyl, ethyl, prop-2-yl or trifluoromethyl.
Preferably, R3 is ethyl.
Preferably, X is xe2x80x94CH2xe2x80x94, xe2x80x94CHR11xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94SO2xe2x80x94.
Preferably, X is xe2x80x94CH2xe2x80x94, xe2x80x94CH(OCH3)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94SO2xe2x80x94.
Preferably, X is xe2x80x94CH2xe2x80x94 or xe2x80x94Sxe2x80x94.
Preferably, R6 is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morphoninyl, piperazinyl, diazepinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl or pyrazinyl each being optionally substituted by xe2x80x94OR5, xe2x80x94NR5R5, xe2x80x94CN, oxo, C1-C6 alkyl, C3-C7 cycloalkyl, xe2x80x94COR7 or halo.
Preferably, R6 is furan-2-yl, 2,4-dihydroxypyrimidinyl, 1-methylimidazolyl, tetrahydrofuranyl, 1,5-dimethylpyrazolyl, tetrazolyl, pyridinyl, pyrimidinyl, 3-hydroxypyridazinyl, 2-hydroxypyridinyl, 2-oxo-2H-pyranyl or 1,2,3-thiadiazolyl.
Preferably, R6 is 2,4-dihydroxypyrimidinyl, 1-methylimidazolyl, tetrahydrofuranyl, 1,5-dimethylpyrazolyl, tetrazolyl, pyridinyl, pyrimidinyl, 3-hydroxypyridazinyl, 2-hydroxypyridinyl, 2-oxo-2H-pyranyl or 1,2,3-thiadiazolyl.
Preferably, R10 is C1-C6 alkyl, phenyl, or C-linked R6, said C1-C6 alkyl and phenyl being optionally substituted by halo, xe2x80x94OR5, xe2x80x94OR12, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94C(xe2x95x90NR5)NR5OR5, xe2x80x94CONR5NR5R5, xe2x80x94OCONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5R12, xe2x80x94NR5COR5, xe2x80x94NR5CO2R7, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5, xe2x80x94NR5SO2R7, xe2x80x94SO2NR5R5 or R6.
Preferably, R10 is C1-C6 alkyl, phenyl, or C-linked R6, said C1-C6 alkyl and phenyl being optionally substituted by halo, xe2x80x94OR5, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CONR5R5, xe2x80x94OCONR5R5, xe2x80x94OCONR5CO2R7, xe2x80x94NR5R5, xe2x80x94NR5CONR5R5, xe2x80x94NR5COCONR5R5 or R6.
Preferably, R10 is C1-C3 alkyl, phenyl, or R6, said C1-C3 alkyl and phenyl being optionally substituted by fluoro, xe2x80x94OH, xe2x80x94O(C1-C6 alkyl), xe2x80x94CN, xe2x80x94CO2(C1-C6 alkyl), xe2x80x94CONH2, xe2x80x94OCONH2, xe2x80x94OCONHCO2Ph, xe2x80x94NH2, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94NHCONH2, xe2x80x94NHCOCONH2 or R6.
Preferably, R10 is xe2x80x94CH2OH, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2CH2OH, xe2x80x94CH2OCONH2, xe2x80x94H2CH2OCONH2, xe2x80x94CH2OCONHCO2Ph, xe2x80x94CH2CO2CH2CH3, xe2x80x94CH2CH2CO2CH3, xe2x80x94CH2CH2CO2CH2CH3, xe2x80x94CH2CH2CONH2, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2CH2NH2, xe2x80x94CHF2, xe2x80x94CH2CN, xe2x80x942N(CH3)2, xe2x80x94CH2OCH3, xe2x80x94CH2OH, xe2x80x94CH2OCH2CH3, CH2NHCONH2, xe2x80x94CH2CH2CH3, phenyl, 2,6-difluorophenyl, 2,4-dihydroxypyrimidin-5-yl, 1-methylimidazol-4-yl, tetrahydrofuran-2-yl, 1,5-dimethylpyrazol-3-yl, xe2x80x94CH2(tetrazol-1-yl), pyridin-2-yl, pyrimidin-2-yl, 2-fluorophenyl, 3-hydroxyphenyl, 3-hydroxypyridazin-6-yl, 2-hydroxypyridin-6-yl, 2-oxo-2H-pyran-5-yl or 1,2,3-thiadiazol-4-yl.
Preferably, R10 is methyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2CH2OH, xe2x80x94CH2CH2NH2,
xe2x80x94CH2CH2CH2NH2, xe2x80x94CH2CN, xe2x80x94CH2CH2OCH3, xe2x80x94CH2CONH2, xe2x80x94CH2CH2NHCOCH2OCH3 or azetidin-3-yl.
The following preferred features of the invention relate to compounds of the formula (I).
Preferably, R4 is phenyl optionally substituted by R6, halo, xe2x80x94CN, C1-C6 alkyl, fluoro-(C1-C6)-alkyl, C3-C7 cycloalkyl or C1-C6 alkoxy.
Preferably, R4 is phenyl substituted by halo, xe2x80x94CN or C1-C3 alkyl.
Preferably, R4 is phenyl substituted by fluoro, chloro, bromo, xe2x80x94CN, or methyl.
Preferably, R4 is 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 3,5-dichlorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 3,5-dicyanophenyl, 3,5-dibromophenyl or 3,5-dimethylphenyl.
Preferably, R4 is (i) phenyl substituted at the 3 position by fluoro, chloro, methyl or cyano or (ii) phenyl substituted at the 3 and 5 positions by two substituents independently chosen from fluoro, chloro, methyl and cyano.
The following preferred features of the invention relate to compounds of the formula (Ib).
Preferably, R4 is phenyl substituted by at least one substituent selected from halo, xe2x80x94CN, C1-C6 alkyl, fluoro-(C1-C6)-alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy.
Preferably, R4 is phenyl substituted by at least one substituent selected from halo, xe2x80x94CN and C1-C3 alkyl.
Preferably, R4 is phenyl substituted by at least one substituent selected from fluoro, chloro, bromo, xe2x80x94CN and methyl.
Preferably, R4 is 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 3,5-dichlorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 3,5-dicyanophenyl, 3,5-dibromophenyl or 3,5-dimethylphenyl.
Preferably, R4 is (i) phenyl substituted at the 3 position by fluoro, chloro, methyl or cyano or (ii) phenyl substituted at the 3 and 5 positions by two substituents independently chosen from fluoro, chloro, methyl and cyano.
All of the compounds of the formula (I) and the compounds of the formula (Ib) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (Ib).
In the following general methods, R1, R2, R3, R4 and X are as previously defined for a compound of the formula (Ib) or a compound of the formula (I) unless otherwise stated.
Compounds of the formula (Ib) and compounds of the formula (I) in which R1 and R3 are each either H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, xe2x80x94CO2R5, xe2x80x94CONR5R5, or C-linked R6, optionally substituted where allowed, may be prepared by the reaction of a compound of the formula 
with a compound of the formula
H2NNHR2xe2x80x83xe2x80x83(III),
or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (II) in a suitable solvent, such as ethanol, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.
Functional equivalents of compounds of the formula (II) may also be used in this reaction. These include compounds of the formula (IV) or (V), in which L1 and L2, respectively, are each suitable leaving groups, preferably xe2x80x94N(C1-C6 alkyl)2, most preferably xe2x80x94N(CH3)2. 
Thus, a compound of the formula (Ib) or a compound of the formula (I) may be prepared by the condensation of a compound of the formula (IV) or (V) with a compound of the formula (III), or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (IV) or (V) in a suitable solvent, such as acetic acid, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux. Compounds of the formula (IV) or (V) are particularly suitable for the synthesis of compounds of the formula (Ib) or compounds of the formula (I) in which R1 or R3, respectively, is H.
Compounds of the formula (IV) in which R1 is H and L1 is dimethylamino may be prepared by the reaction of a compound of the formula (VI) with dimethylformamide dimethylacetal at an elevated temperature, preferably at about 100xc2x0 C. Compounds of the formula (V) in which R3 is H and L2 is dimethylamino may be prepared by the reaction of a compound of the formula (VII) under the same conditions. Other compounds of the formula (IV) or (V) in which L1 or L2 is dimethylamino may be prepared analogously.
Compounds of the formula (VI) are either commercially available or may be prepared 
by methods well know in the art. For example, where X is S, compounds of the formula (VI) may be prepared by the reaction of a compound of the formula
R3COCH2Brxe2x80x83xe2x80x83(VIII)
with a compound of the formula
R4SHxe2x80x83xe2x80x83(IX).
In a typical procedure a solution of a compound of the formula (VIII) in a suitable solvent, such as acetone, is treated with a compound of the formula (IX), optionally treated with a base, such as potassium carbonate and optionally treated with a catalyst such as sodium iodide or tetrabutylammonium iodide. The reaction is preferably performed at room temperature.
Compounds of the formula (VII) are either commercially available or may be prepared from a compound of the formula
R1COCH2Brxe2x80x83xe2x80x83(X)
and a compound of the formula (IX) in the same way that a compound of the formula (VI) may be prepared from a compound of the formula (VIII).
Compounds of the formula (II) may be prepared using the route shown in Scheme 1 in which L3 is a suitable leaving group, preferably chloro. 
In Scheme 1, compounds of the formula (II) in which X is xe2x80x94CH2xe2x80x94 may be prepared by the reduction of a compound of the formula (XI) with a suitable reducing agent such as (a) hydrogen in the presence of a palladium catalyst, (b) diphenylsilane in the presence of a palladium catalyst and a zinc salt or (c) triethylsilane in the presence of an acid such as trifluoroacetic acid. In a typical procedure, a solution of the compound of the formula (XI) in a suitable solvent, such as ethanol or a mixture of ethanol and ethyl acetate, under a hydrogen atmosphere, is treated with 5% w/w palladium on barium sulphate. In another typical procedure, a solution of the compound of the formula (XI) in a suitable solvent, such as dichloromethane, is treated with diphenylsilane, tetrakis(triphenylphosphine)palladium (0) and zinc chloride. In a further typical example, a solution of the compound of the formula (XI) in a suitable solvent, such as dichloromethane, is treated with triethylsilane and trifluoroacetic acid.
Compounds of the formula (XI) may be prepared by the condensation of a compound of the formula (XII) with a compound of the formula
R4CHOxe2x80x83xe2x80x83(XV),
or a functional equivalent thereof, such as an acetal, optionally in the presence of a suitable catalyst, such as a mixture of acetic acid and piperidine In a typical procedure, a solution of the compound of the formula (XII) in a suitable solvent such as toluene is treated with a compound of the formula (XV), acetic acid and piperidine and heated at a temperature of from room temperature to the reflux temperature of the solvent. Preferably, the reaction mixture is heated under reflux using a Dean-Stark apparatus. Compounds of the formula (XI), prepared in this way, in which R1 and R3 are different, are usually formed as a mixture of stereoisomers. Such a mixture may be used directly in subsequent transformations or separated into its individual stereoisomers which may then be used separately.
Alternatively, compounds of the formula (II) in which X is xe2x80x94CH2xe2x80x94 may be prepared by the reaction of a compound of the formula (XII) with a compound of the formula
R4CH2L6xe2x80x83xe2x80x83(XXVIII)
in which L6 is a suitable leaving group, preferably is chloro, bromo, iodo or para-toluenesulphonate, in the presence of a suitable base. In a typical procedure, a solution of the compound of the formula (XII) in a suitable solvent, such as 2-butanone, tetrahydrofuran, acetonitrile or diethylether, is treated with a base, such as sodium ethoxide, sodium hydride or sodium carbonate, and the compound of the formula (XXVIII), optionally with heating. A preferred combination is 2-butanone as the solvent and sodium hydride as the base.
Compounds of the formula (XII) and compounds of the formula (XXVIII) are either commercially available or are easily prepared by methods well known to the skilled person.
Compounds of the formula (II) in which X is xe2x80x94CHR10xe2x80x94 (other than where R10 is C1-C6 alkoxyxe2x80x94see below for the preparation of these compounds) may be prepared by the reduction of a compound of the formula (XIII) with a suitable reducing agent such as (a) hydrogen in the presence of a palladium catalyst, (b) diphenylsilane in the presence of a palladium catalyst and a zinc salt or (c) triethylsilane in the presence of an acid such as trifluoroacetic acid. In a typical procedure, a solution of the compound of the formula (XIII) in a suitable solvent, such as ethanol or a mixture of ethanol and ethyl acetate, under a hydrogen atmosphere, is treated with 5% w/w palladium on barium sulphate. In another typical procedure, a solution of the compound of the formula (XIII) in a suitable solvent, such as dichloromethane, is treated with diphenylsilane, tetrakis(triphenylphosphine)palladium (0) and zinc chloride. In a further typical example, a solution of the compound of the formula (XIII) in a suitable solvent, such as dichloromethane, is treated with triethylsilane and trifluoroacetic acid.
Compounds of the formula (XIII) may be prepared by the condensation of a compound of the formula (XII) with a compound of the formula
R4COR10xe2x80x83xe2x80x83(XVI),
or a functional equivalent thereof, such as a ketal, optionally in the presence of a suitable catalyst, such as a mixture of acetic acid and piperidine. In a typical procedure, a solution of the compound of the formula (XII) in a suitable solvent such as toluene is treated with a compound of the formula (XVI), acetic acid and piperidine and heated at a temperature of from room temperature to the reflux temperature of the solvent. Preferably, the reaction mixture is heated under reflux using a Dean-Stark apparatus. Compounds of the formula (XIII), prepared in this way, in which R1 and R3 are different, are usually formed as a mixture of stereoisomers. Such a mixture may be used directly in subsequent transformations or separated into its individual stereoisomers which may then be used separately.
Compounds of the formula (II) in which X is xe2x80x94Sxe2x80x94 may be prepared by the reaction of a compound of the formula (XIV) with a compound of the formula (IX). In a typical procedure a solution of a compound of the formula (XIV) in a suitable solvent, such as acetone, is treated with a compound of the formula (IX), optionally treated with a base, such as potassium carbonate and optionally treated with a catalyst such as sodium iodide or tetrabutylammonium iodide. The reaction is preferably performed at room temperature.
Compounds of the formula (XIV) may be prepared by the reaction of a compound of the formula (XII) with a suitable activating agent, e.g. in the case where L3 is chloro, with a chlorinating agent such as sulphuryl chloride. In a typical procedure, where L3 is chloro, the compound of the formula (XII) is treated with sulphuryl chloride, optionally in the presence of a suitable solvent such as dichloromethane.
Compounds of the formula (Ib) and compounds of the formula (I) in which R1 or R3 is xe2x80x94OR7 may be prepared using the route shown in Scheme 2 in which Ra is C1-C6 alkyl and L4 is a suitable leaving group, preferably trifluoromethanesulphonate. 
In Scheme 2, compounds of the formula (Ib) and compounds of the formula (I) in which R1 is xe2x80x94OR7 may be prepared by the reaction of a compound of the formula (XVII) with an alcohol of the formula
R7OHxe2x80x83xe2x80x83(XXV)
in the presence of a suitable catalyst, preferably a palladium catalyst, and carbon monoxide. In a typical procedure a mixture of the compound of the formula (XVII), a suitable palladium catalyst such as 1,1xe2x80x2-bis(diphenylphosphino)ferrocenepalladium(II)chloride, the alcohol of the formula (XXV) and, optionally, a suitable solvent such as N,N-dimethylformamide is heated, preferably to about 50xc2x0 C., under an atmosphere of carbon monoxide, preferably at a pressure of 345 kPa.
Compounds of the formula (XVII) may be prepared by the derivatisation of a compound of the formula (XVIII). In the case where L4 is trifluoromethanesulphonate a suitable derivatising agent is phenyltriflamide. In a typical procedure, where L4 is trifluoromethanesulphonate, a solution of the compound of the formula (XVIII) and a suitable base, preferably a trialkylamine base such as triethylamine, in a suitable solvent such as dichloromethane is treated with phenyltriflamide.
Compounds of the formula (XVIII) may be prepared by the reaction of a compound of the formula (XIX) with a compound of the formula (III), or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (XIX) in a suitable solvent, such as ethanol, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.
Compounds of the formula (XIX) may be prepared by the derivatisation of a compound of the formula (XX) in the same way that compounds of the formula (II) may be prepared by the derivatisation of a compound of the formula (XII) as described above.
Compounds of the formula (XX) are either commercially available or are readily prepared by methods well known to the skilled person.
In Scheme 2, compounds of the formula (Ib) and compounds of the formula (I) in which R3 is xe2x80x94OR7 may be prepared from a compound of the formula (XXIV) in the same way that a compound of the formula (I) or a compound of the formula (Ib) in which R1 is xe2x80x94OR7 is prepared from a compound of the formula (XX), as described above, mutatis mutandis.
The skilled man will appreciate that compounds of the formula (XVIII) and compounds of the formula (XXII) may exist in one of several tautomeric forms.
Alternatively, compounds of the formula (Ib) and compounds of the formula (I) in which R1 or R3 is xe2x80x94OR7 may be prepared from compounds of the formula (XVIII) or (XXII), respectively, by reaction with a compound of the formula (XXV) under dehydrating conditions, e.g. using the Mitsunobu reaction. In a typical procedure, a solution of the compound of the formula (XVIII) or (XXII) in a suitable solvent, such as tetrahydrofuran is treated with a dialkylazodicarboxylate, preferably diethylazodicarboxylate, a triarylphosphine, preferably triphenylphosphine and a compound of the formula (XXV).
Alternatively, compounds of the formula (Ib) and compounds of the formula (I) in which R1 or R3 is xe2x80x94OR7 may be prepared from compounds of the formula (XVIII) or (XXII), respectively, by reaction with a compound of the formula
R7L7xe2x80x83xe2x80x83(XXIX)
in which L7 is a suitable leaving group, preferably halo, optionally in the presence of a suitable base. In a typical procedure, a solution of the compound of the formula (XVIII) or the compound of the formula (XXII) in a suitable solvent, such as tetrahydrofuran, dimethylformamide or ethanol, is treated with a base, such as sodium ethoxide or sodium carbonate, and the compound of the formula (XXIX), optionally with heating.
Compounds of the formula (Ib) and compounds of the formula (I) in which R1 or R3 is halo may be prepared by the reaction, respectively, of a compound of the formula (XVIII) or a compound of the formula (XXII) with a suitable halogenating agent. In a typical procedure, the compound of the formula (XVIII) or (XXII) is treated with POCl3, optionally in the presence of a suitable solvent such as dimethylformamide, to give a compound of the formula (Ib) or a compound of the formula (I) in which R1 or R3, respectively, is chloro.
Compounds of the formula (Ib) and compounds of the formula (I) in which R1 or R3 is xe2x80x94OCONR5R5 may be prepared by the reaction, respectively, of a compound of the formula (XVIII) or a compound of the formula (XXII) with a compound of the formula
R5R5NCOL5xe2x80x83xe2x80x83(XXVI)
in which L5 is a suitable leaving group, preferably chloro, or, in the case where one of the R5 groups is H, with a compound of the formula
R5Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(XXVII).
Compounds of the formula (Ib) and compounds of the formula (I) in which R1 or R3 is xe2x80x94NH2 may be prepared by the route shown in Scheme 3. 
In Scheme 3, compounds of the formula (Ib) and compounds of the formula (I) in which R1 is xe2x80x94NH2 may be prepared by the reaction of a compound of the formula (XXX) with a compound of the formula (III), or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (XXX) in a suitable solvent, such as ethanol, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.
Compounds of the formula (XXX) may be prepared from a compound of the formula (XXXI) in the same way that compounds of the formula (II) may be prepared from a compound of the formula (XII) as described above.
Compounds of the formula (XXXI) are either commercially available or readily prepared by methods well known to the skilled person.
In Scheme 3, compounds of the formula (Ib) and compounds of the formula (I) in which R3 is xe2x80x94NH2 may be prepared from a compound of the formula (XXXIII) in the same way that compounds of the formula (Ib) and compounds of the formula (I) in which R1 is NH2 may be prepared from compounds of the formula (XXXI), mutatis mutandis.
Compounds of the formula (Ib) and compounds of the formula (I) in which X is xe2x80x94COxe2x80x94 or xe2x80x94CHR10xe2x80x94 and R10 is C1-C6 alkoxy may be prepared by the route shown in Scheme 4 in which Rb is C1-C6 alkyl. 
In Scheme 4, compounds of the formula (Ib) and compounds of the formula (I) in which X is xe2x80x94COxe2x80x94 (i.e. compounds of the formula (Ic)) may be prepared by the oxidation of a compound of the formula (XXXIV). In a typical procedure, a solution of a compound of the formula (XXXIV) in a suitable solvent, such as dichloromethane, is treated with N-methylmorpholine-N-oxide and tetra-n-propylammonium perruthenate(VII).
Compounds of the formula (Ib) and compounds of the formula (I) in which X is xe2x80x94CHR10xe2x80x94 and R10 is C1-C6 alkoxy (i.e. compounds of the formula (Id)) may be prepared by the alkylation of a compound of the formula (XXXIV). In a typical procedure, a solution of a compound of the formula (XXXIV) in a suitable solvent, such as N,N-dimethylformamide, is treated with a base, such as sodium hydride, and a compound of the formula
RbL8xe2x80x83xe2x80x83(XXXVIII)
wherein Rb is C1-C6 alkyl and L8 is a suitable leaving group, preferably chloro, bromo or iodo.
Compounds of the formula (XXXIV) may be prepared by the reaction of a compound of the formula (XXXV) with a suitable metal or organometallic reagent to form an organometallic intermediate which is reacted with a compound of the formula (XV). A preferred metal is magnesium. In a typical procedure, a solution of the compound of the formula (XXXV) in a suitable solvent, such as tetrahydrofuran, is treated with an alkylmagnesium chloride, e.g. iso-propylmagnesium chloride, preferably with cooling in an ice bath, and a compound of the formula (XV) is added.
Compounds of the formula (XXXV) may be prepared by the reaction of a compound of the formula (XXXVI) with a suitable base, preferably sodium hydride, and the addition of a compound of the formula
R2L9xe2x80x83xe2x80x83(XXXIX)
wherein L9 is a suitable leaving group, preferably a chloro, bromo, iodo or tosylate group. In a typical procedure, a solution of the compound of the formula (XXXVI) in a suitable solvent, such as N,N-dimethylformamide, is treated firstly with a suitable base, such as sodium hydride, and then with a compound of the formula (XXXIX). The reaction is then preferably heated, most preferably to 50xc2x0 C. If R2 contains a free xe2x80x94OH, xe2x80x94NH2, or xe2x80x94NHxe2x80x94 group then a protecting group is preferably employed to mask such functionality. Examples of suitable protecting groups will be apparent to the skilled person [see, for instance, xe2x80x98Protecting groups in Organic Synthesis (Second Edition)xe2x80x99 by Theodora W. Green and Peter G. M. Wuts, 1991, John Wiley and Sons]. The protecting group may be removed immediately or carried through subsequent steps, as described above, and removed as a final step (see below).
Compounds of the formula (XXXVI) may be prepared by the reaction of a compound of the formula (XXXVII) with a suitable iodinating agent. In a typical procedure, a solution of the compound of the formula (XXXVII) in a suitable solvent, such as dichloromethane, is treated with the iodinating agent which is preferably N-iodosuccinimide.
Compounds of the formula (XXXVII) are either commercially available or are readily prepared by methods well known to the skilled man. Such compounds may, for instance, be prepared by analogy with the methods presented above, for example by the reaction of a diketone (XII) with a compound of the formula (III), or a salt or solvate thereof.
It will be appreciated by those skilled in the art that, in many cases, compounds of the formula (Ib) and compounds of the formula (I) may be converted, respectively, into other compounds of the formula (Ib) or compounds of the formula (I) by functional group transformations. For instance:
(a) Compounds of the formula (Ib)/(I) in which R2 is H may be converted into compounds of the formula (Ib)/(I) in which R2 is optionally substituted C1-C6 alkyl by reaction with an appropriate alkylating agent. In a typical procedure, a solution of a compound of the formula (Ib)/(I) in which R2 is H in a suitable solvent such as ethanol or N,N-dimethylformamide is treated with an alkyl bromide and a base such as sodium ethoxide or sodium hydride and heated at a temperature of from room temperature to the reflux temperature of the solvent. A preferred combination is N,N-dimethylformamide as the solvent, sodium hydride as the base and room temperature as the temperature. Examples of specific alkylating agents include bromoacetonitrile, ethyl 4-chloroacetoacetate, ethyl bromoacetate, methyl bromoacetate and chloroethylamine hydrochloride. The use of further specific alkylating agents is illustrated by the Examples below.
(b) Compounds of the formula (Ib)/(I) in which R2 contains as ester functionality may be reduced with a suitable reducing agent, such as lithium aluminium hydride, to give corresponding compounds of the formula (Ib)/(I) in which R2 contains a hydroxy group. In a typical procedure, a solution of the compound of the formula (Ib)/(I), in which R2 contains an ester group, in a suitable solvent, such as diethyl ether, is treated with lithium aluminium hydride, preferably with cooling to a temperature of from xe2x88x9278xc2x0 C. to 0xc2x0 C.
(c) Compounds of the formula (Ib)/(I) in which R1 or R3 is xe2x80x94NH2, may be converted into compounds of the formula (Ib)/(I) in which R1 or R3, respectively, is xe2x80x94NHRc, where Rc is C1-C6 alkyl, C3-C8 cycloalkyl or benzyl by a reductive amination with an appropriate aldehyde or ketone. In a typical reductive amination, the reaction will proceed in a suitable solvent such as dichloromethane, in the presence of a suitable reducing agent such as sodium triacetoxyborohydride and optionally in the presence of an acid such as acetic acid. A further reductive amination may be performed on a compound of the formula (Ib)/(I) in which R1 or R3 is xe2x80x94NHRc to give a compound of the formula (Ib)/(I) in which R1 or R3, respectively, is xe2x80x94NRcRc, where Rc is as defined above and each Rc may be the same or different.
(d) Compounds of the formula (Ib)/(I) in which R1 or R3 is xe2x80x94NHR5, may be converted into compounds of the formula (Ib)/(I) in which, respectively, R1 is xe2x80x94NR5COR5, xe2x80x94NR5CONR5R5, xe2x80x94NR5CO2R7 or xe2x80x94NR5SO2R7 or R3 is xe2x80x94NR5COR5, xe2x80x94NR5CONR5R5, xe2x80x94NR5CO2R7 or xe2x80x94NR5SO2R7 by reaction with an appropriate acylating or sulphonylating agent in a suitable inert solvent, such as dichloromethane, optionally in the presence of a base, preferably a tertiary amine base such as triethylamine.
(e) compounds of the formula (Ib)/(I) in which R1 or R3 is xe2x80x94CO2R5, wherein R5 is other than H, may be converted into compounds of the formula (Ib)/(I) in which R1 or R3, respectively, is xe2x80x94CO2H by hydrolysis. Typically the reaction will be carried out in a suitable solvent, such as aqueous ethanol, or aqueous 1,4-dioxan and in the presence of a base such as sodium hydroxide. Such an acid may be converted to a primary amide by reaction with ammonia and a suitable coupling agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide. Such a primary amide may then be converted into a nitrile by dehydration with a suitable dehydrating agent, such as phosphoryl chloride.
(f) Compounds of the formula (Ib)/(I) in which R1 or R3 is xe2x80x94CO2H, may be converted into compounds of the formula (Ib)(I) in which R1 or R3, respectively, is xe2x80x94NH2, by the Curtius rearrangement. In a typical procedure, the reaction is carried out in a suitable solvent, such as dichloromethane, in the presence of a reagent such as diphenylphosphoryl azide.
(g) Compounds of the formula (Ib)/(I) in which X is xe2x80x94Sxe2x80x94 may be converted into compounds of the formula (Ib)/(I) in which X is xe2x80x94SOxe2x80x94 by reaction with a suitable oxidising agent, such as meta-chloroperoxybenzoic acid. The reaction is carried out in the presence of a suitable solvent such as dichloromethane.
(h) Compounds of the formula (Ib)/(I) in which X is xe2x80x94Sxe2x80x94 may be converted into compounds of the formula (Ib)/(I) in which X is xe2x80x94SO2xe2x80x94 by reaction with a suitable oxidising agent such as Oxone (trade mark), meta-chloroperoxybenzoic acid or hydrogen peroxide. In a typical procedure, a solution of the compound of the formula (Ib)/(I) in which X is xe2x80x94Sxe2x80x94 in a suitable solvent, such as dichloromethane, is treated with meta-chloroperoxybenzoic acid.
(i) Compounds of the formula (Ib)/(I) in which R1, R2 or R3 contain a heterocycle of the formula R6 may be prepared by standard heterocycle-forming reactions well known to the skilled person (see, for example, Advanced Organic Chemistry, 3rd Edition, by Gerry March or Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Volumes 1-11), either from another compound of the formula (Ib)/(I) or otherwise. For instance, compounds of the formula (Ib)/(I) in which R2 is (2-amino-6-hydroxypyrimidin-4-yl)methyl may be prepared by the sequential reaction of a compound of the formula (Ib)/(I) in which R2 is H with methyl 4-chloroacetoacetate and then guanidine hydrochloride.
(j) Compounds of the formula (Ib)/(I) in which either R1 or R3 is an N-linked heterocycle of the formula R6 may be prepared from compounds of the formula (Ib)/(I) in which R1 or R3, respectively, is xe2x80x94NH2, by standard heterocycle-forming reactions well known to the skilled man (see, for example, Advanced Organic Chemistry, 3rd Edition, by Gerry March or Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Volumes 1-11).
Compounds of the formula (Ib)/(I) containing an xe2x80x94OH, xe2x80x94NHxe2x80x94 or xe2x80x94NH2 group may be prepared by the deprotection of the corresponding compound bearing an xe2x80x94OP1, xe2x80x94NP1xe2x80x94 or xe2x80x94NHP1 group, respectively, wherein the group P1 is a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see, for instance, xe2x80x98Protecting groups in Organic Synthesis (Second Edition)xe2x80x99 by Theodora W. Green and Peter G. M. Wuts, 1991, John Wiley and Sons]. Such compounds bearing an xe2x80x94OP1, xe2x80x94NP1xe2x80x94 or xe2x80x94NHP1 group may be prepared using the routes described above, mutatis mutandis.
The compounds of the formula (I) and the compounds of the formula (Ib) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the formula (I) and the compounds of the formula (Ib) can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The compounds of the formula (I) and the compounds of the formula (Ib) may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of the compounds of the formula (I) and the compounds of the formula (Ib) may be in coated or uncoated form, as desired.
Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
A formulation of the tablet could typically contain between about 0.01 mg and 500 mg of active compound whilst tablet fill weights may range from 50 mg to 1000 mg. An example of a formulation for a 10 mg tablet is illustrated below:
The tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process. The tablet cores may be coated with appropriate overcoats.
Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the formula (I) and the compounds of the formula (Ib) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
The compounds of the formula (I) and the compounds of the formula (Ib) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) and the compounds of the formula (Ib) will usually be from 0.01 to 30 mg/kg, preferably from 0.01 to 10 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the formula (I) or the compound of the formula (Ib) may contain from 1 to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will appreciate that, in the treatment of certain conditions the compounds of the formula (I) and the compounds of the formula (Ib) may be taken as a single dose as needed or desired.
The compounds of formula (I) and the compounds of the formula (Ib) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insulator may be formulated to contain a powder mix of a compound of the formula (I) or a compound of the formula (Ib) and a suitable powder base such as lactose or starch.
Alternatively, the compounds of the formula (I) and the compounds of the formula (Ib) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the formula (I) and the compounds of the formula (Ib) may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes.
They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the formula (I) and the compounds of the formula (Ib) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the formula (I) and the compounds of the formula (Ib) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
Oral administration is preferred.
Included within the scope of the present invention are embodiments comprising the co-administration of a compound of the present invention with one or more additional therapeutic agents, and compositions containing a compound of the present invention along with one or more additional therapeutic agents. Such a combination therapy is especially useful for the treatment of infection by HIV and related retroviruses which may evolve rapidly into strains resistant to any monotherapy. Alternatively, additional therapeutic agents may be desirable to treat diseases and conditions which result from or accompany the disease being treated with the compound of the present invention. For example, in the treatment of an HIV or related retroviral infection, it may be desirable to additionally treat opportunistic infections, neoplasms and other conditions which occur as a result of the immuno-compromised state of the patient being treated.
Preferred combinations of the present invention include simultaneous or sequential treatment with a compound of the formula (I) or a compound of the formula (Ib), as defined above, or a pharmaceutically acceptable salt thereof, and:
(a) one or more reverse transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir, combivir or trizivir;
(b) one or more non-nucleoside reverse transcriptase inhibitors such as nevirapine, delavirdine or efavirenz;
(c) one or more HIV protease inhibitors such as indanivir, ritonavir, saquinavir or nelfinavir;
(d) one or more CCR5 antagonists such as TAK-779 or SCH-351125;
(e) one or more CXCR4 antagonists such as AMD-3100;
(f) one or more integrase inhibitors;
(g) one or more inhibitors of viral fusion such as T-20 or T-1249;
(h) one or more investigational drugs such as KNI-272, amprenavir, GW-33908, FTC, PMPA, S-1153, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690, ABT-378, KNI-764, DPC-083, TMC-120 or TMC-125; or
(i) one or more antifungal or antibacterial agents such as fluconazole.
The activity of the compounds of the invention as reverse transcriptase inhibitors and as agents for treating HIV infections may be measured using the following assays.
A. Inhibition of HIV-1 Reverse Transcriptase Enzyme
The reverse transcriptase activity of the compounds of the invention may be assayed as following. Using the purified recombinant HIV-1 reverse transcriptase (RT, EC, 2.7.7.49) obtained by expression in Escherichia Coli, a 96-well plate assay system was established for assaying a large number of samples using either the Poly(rA)-oligo(dT) Reverse Transcriptase [3H]-SPA enzyme assay system (Amersham NK9020) or the [3H]-flashplate enzyme assay system (NEN-SMP 103) and following the manufacturer""s recommendations. The compounds were dissolved in 100% DMSO and diluted with the appropriate buffer to a 5% final DMSO concentration. The inhibitory activity was expressed in percent inhibition relative to the DMSO control. The concentration at which the compound inhibited the reverse transcriptase by 50% was expressed as the IC50 of the compound.
B. Anti-Human Immunodeficiency Virus (HIV-1) Cell Culture Assay
The anti-HIV activity of the compounds of the invention may be assayed by the following procedures.
1) SupT1 cells were cultured in an RPMI-1640 medium supplemented with 10% foetal calf serum and were split so that they were in growth phase on the day of use.
2) The compounds were dissolved in 100% DMSO and diluted with the above culture medium to predetermined concentrations and distributed in 20 xcexcl aliquots into a 96-well microtiter plate (0.1% DMSO final concentration).
3) To prepare infected cells, 100 xcexcl of RF viruses (TCID50 of 107/ml) were added to 106 cells and incubated for 1 hour at 37xc2x0 C. The cells were then washed twice in PBS and resuspended in the culture medium at a density of 2.2xc3x97105 cells/ml. 180 xcexcl of these infected cells was transferred to wells of the 96 well plate containing the compounds.
4) The plate was incubated in a CO2 incubator at 37xc2x0 C. for 4 days. The cell survival rates were measured following the manufacturer""s recommendations (CellTiter 96(copyright) AQueous Non-Radioactive Assayxe2x80x94Promega (cat no: G5430)). The concentration at which the compound inhibited the cytotoxic effect of the virus by 50% was expressed as the EC50.
Thus the invention provides:
(i) the use of a compound of the formula (I) or a compound of the formula (Ib) or a pharmaceutically acceptable salt or solvate of either in the manufacture of a reverse transcriptase inhibitor or modulator;
(ii) the use of a compound of the formula (I) or a compound of the formula (Ib), or a pharmaceutically acceptable salt or solvate of either in the manufacture of a medicament for the treatment of a human immunodeficiency viral (HIV), or genetically related retroviral, infection or a resulting acquired immunodeficiency syndrome (AIDS);
(iii) a compound of the formula (I) or a compound of the formula (Ib), or a pharmaceutically acceptable salt or solvate of either, for use as a reverse transcriptase inhibitor;
(iv) a compound of the formula (I) or a compound of the formula (Ib) or a pharmaceutically acceptable salt or solvate of either, for use in the treatment of a human immunodeficiency viral (HIV), or genetically related retroviral, infection or a resulting acquired immunodeficiency syndrome (AIDS);
(v) a method of treatment or prevention of a disorder treatable by the inhibition of reverse transcriptase, comprising the administration of an effective amount of a compound of the formula (I) or a compound of the formula (Ib), or a pharmaceutically acceptable salt or solvate of either, to a patient in need of such treatment;
(vi) a method of treatment of a human immunodeficiency viral (HIV), or genetically related retroviral, infection or a resulting acquired immunodeficiency syndrome (AIDS) comprising the administration of an effective amount of a compound of the formula (I) or a compound of the formula (Ib), or a pharmaceutically acceptable salt or solvate of either, to a patient in need of such treatment;
(vii) a compound of the formula (Ib) or a pharmaceutically acceptable salt or solvate thereof;
(viii) a process for the preparation of a compound of the formula (Ib) or a pharmaceutically acceptable salt or solvate thereof;
(ix) a pharmaceutical composition including a compound of the formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
(x) a compound of the formula (Ib) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament;